Process for the preparation of α-chloromethylene-triorganylphosphorane derivatives

ABSTRACT

A process for the preparation of α-chloromethylene-triorganylphosphorane derivatives I                    
     (radicals R are  C -organic substituents and A stands for  CN  or  CO -B where B is a  C -organic or  O -organic radical which is inert under chlorination conditions) by chlorination of phosphoranes II                    
     with chlorine, wherein the chlorination is carried out in the presence of a mineral base as hydrogen chloride acceptor and the chlorine and base are fed to the reaction mixture concurrently but separately at the rates at which they are consumed. 
     The reaction products I are important intermediates for plant protectants.

DESCRIPTION

The present invention relates to an improved process for the preparationof α-chloromethylene-triorganylphosphorane derivatives of the generalformula I

in which the radicals R can be the same or different and denoteC-organic substituents and A stands for cyano or a group CO-B where Bdenotes a C-organic or O-organic radical which has from 1 to 12 carbonatoms and is inert under chlorination conditions, by chlorination ofphosphoranes of formula II

with chlorine.

It is well known that phosphoranes 11 can be chlorinated to formα-chloromethylene-triphenylphosphorane derivatives (cf Houben-Weyl,Methoden der Organischen Chemie, Vol. E1, Georg Thieme Verlag 1982, pp636-639).

According to G.Märkl [Chem. Ber. 94, 2996 (1961)], one procedure is tochlorinate triphenylphosphine-carbomethoxymethylene (II; A=CO—OCH₃) withdiluted chlorine gas or with phenyl iodide chloride. The drawback ofthis method, however, is that the product I can be obtained in a yieldof not more than 50%, because phosphonium chloride IIIa

B—CH₂—P⊕(C₆H₅)₃ Cl⊖  (IIIa),

is formed as a by-product.

D. B. Denney and S. T. Ross [J. Org. Chem. 27, 998 (1962)] describe twoother methods of chlorinating compounds of type II (A=CO—CH₃, CO—OC₂H₅,CO—C₆H₅) in methylene chloride at from −60° to −70° C., in which thechlorinating agent is a solution of chlorine in carbon tetrachloride.

In the first of these two methods, the chlorination is carried out inthe presence of tertiary amines. Apart from the fact that such a methodcalls for elaborate engineering measures on account of the lowtemperatures involved, there is the risk of the formation of explosivenitrogen trichloride via a side reaction of the chlorine with the amine.

The second method operates without a base and initially yields thephosphonium chloride of I [(C₆H₅)₃⊕PCH₂—A Cl⊖] as a solid, which is thenseparated, dissolved in water/acetone and converted to I with sodiumhydroxide. The fact that two stages are necessary to yield the productmakes this method unsatisfactory.

Other known processes [G.Märkl, Chem. Ber. 95, 3003 (1962); J. Bestmannand R. Armsen,Synthesis, 590 (1970) and EP-A 421,225] are uneconomical,because they use chlorinating agents which are either expensive [phenyliodide chloride, sodium p-toluenesulfochloramine (chloramine-T)] orwhich have to be handled as solids (calcium chloride). Furthermore,their use leads to a high proportion of by-products, which must bedisposed of or, if it is desired to recycle them to the process, must beregenerated at high cost.

It was thus an object of the present invention to provide a simple andindustrially economical method of synthesizingα-chloromethylene-triorganylphosphorane derivatives I.

Accordingly, a process for the preparation ofα-chloromethylene-triorganylphosphorane derivatives of the generalformula I

by chlorination of phosphoranes of formula II

with chlorine has been found, wherein the chlorination is carried out inthe presence of a mineral base as hydrogen chloride acceptor and thechlorine and said base are fed to the reaction mixture concurrently butseparately at the rates at which they are consumed.

The process of the invention may be successfully used for the synthesisof all of the α-chloromethylene-triorganylphosphorane derivatives Idefined above, particularly those representatives thereof in which A isa group CO-B where B signifies the following:

hydrogen;

a branched or unbranched C₁-C₄ alkyl group such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl, where the alkylgroup may additionally bear a C₁-C₄ alkoxy group such as methoxy,ethoxy, isopropoxy, and tert-butoxy;

a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group;

a branched or unbranched C₁-C₈ alkoxy group, in particular a C₁-C₆alkoxy group, such as methoxy, ethoxy, n-propoxy, 1-methylethoxy,n-butoxy, 1-methylpropoxy, 2-methylpropoxy, 1,1-dimethylethoxy,n-pentoxy, 1-methyl-butoxy, 2-methylbutoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, n-hexoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy,4-methylpentoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy,1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy,3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy, 1-ethyl-i-methylpropoxy,and 1-ethyl-2-methylpropoxy, and preferably methoxy and ethoxy;

a branched or unbranched C₁-C₆-alkylthio group such as methylthio,ethylthio, n-propylthio, 1-methylethylthio, n-butylthio,1-methylpropylthio, 2-methylpropylthio, 1,1-dimethylethylthio,n-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio,2,2-dimethylpropylthio, 1-ethylpropylthio, n-hexylthio,1,1-dimethylpropylthio, 1 ,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropylthio, and1-ethyl-2-methylpropylthio, and preferably methylthio and ethylthio;

a C₁ -C₆-alkoxi-C₁-C₆ alkoxi group, in particular aC₁-C₄-alkoxy-C₁-C₄-alkoxy group, such as methoxymethoxy, ethoxymethoxy,n-propoxymethoxy, (1-methylethoxy)methoxy, n-butoxymethoxy,(1-methylpropoxy)methoxy, (2-methylpropoxy)methoxy,(1,1-dimethylethoxy)methoxy, methoxyethoxy, ethoxyethoxy,n-propoxyethoxy, (1-methylethoxy)ethoxy, n-butoxyethoxy,(1-methylpropoxy)ethoxy, (2-methylpropoxy)ethoxy,(1,1-dimethylethoxy)ethoxy, 3-(methoxy)propoxy, 2-(methoxy)propoxy, and2-(ethoxy)propoxy, and preferably methoxymethoxy;

an aryl group, an aryloxy group, or an aryl-C₁-C₆-alkoxy group, where ineach case the aryl group may be unsubstituted or can bear a phenylradical or from one to three of the following radicals: C₁-C₄-alkyl,C₁-C₄-alkoxy, nitro, trifluoromethyl and/or halo;

in particular the phenyl group, a C₁-C₄-alkylphenyl group such as o-,m-, p-tolyl, a C₁-C₄-alkoxyphenyl group such as o-, m-, p-methoxyphenyl,a halophenyl group such as o-, m-, p-fluorophenyl, o-, m-,p-chlorophenyl, and o-, m-, p-bromophenyl, the o-, m-, p-nitrophenylgroup, the o-, m-, p-(trifluoromethyl)phenyl group, the o-, m-,p-biphenyl group, the naphthyl group, the phenoxy group, the naphthoxygroup, a phenyl-C₁-C₆-alkoxy group, or a naphthyl-C₁-C₆-alkyl group,such as benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylprop-1-yloxy,2-phenylprop-1-yloxy, 3-phenylprop-1-yloxy, 1-phenylbut-1-yloxy,2-phenylbut-1-yloxy, 3-phenylbut-1-yloxy, 4-phenylbut-1-yloxy,1-phenylbut-2-yloxy, 2-phenylbut-2-yloxy, 3-phenylbut-2-yloxy,4-phenylbut-2-yloxy, 1-(phenylmethyl)eth-1-yloxy,1-(phenylmethyl)-1-(methyl)eth-1-yloxy, 1-(phenylmethyl)prop-1-yloxy,naphthylmethyloxy, 1-naphthylethyloxy, 2-naphthylethyloxy,1-naphthylprop-1-yloxy, 2-naphthylprop-1-yloxy, 3-naphthylprop-1-yloxy,1-naphthylbut-1-yloxy, 2-naphthylbut-1-yloxy, 3-naphthylbut-1-yloxy,4-naphthylbut-1-yloxy, 1-naphthylbut-2-yloxy, 2-naphthylbut-2-yloxy,3-naphthylbut-2-yloxy, 4-naphthylbut-2-yloxy,1-(naphthylmethyl)eth-1-yloxy, 1-(naphthylmethyl)-1-(methyl)eth-1-yloxy,and 1-(naphthylmethyl)prop-1-yloxy, and preferably phenyl, phenoxy,benzyloxy, 2-phenylethoxy, 2-naphthyl, and 2-naphthylethoxy, and each ofsaid phenyl and naphthyl radicals may additionally carry from 1 to 3substituents which are inert under the conditions of the reaction.

The radicals R attached to phosphorus may be the same or different anddenote, for example, branched or unbranched C₁-C₈ alkyl groups, C₅-C₆cycloalkyl groups, and, in particular, phenyl, which can carry furthersubstituents inert to the conditions of the reaction, for example C₁-C₄alkyl such as methyl, ethyl, and tertbutyl, C₁-C₄ alkoxy such asmethoxy, or halogen such as fluorine, chlorine, and bromine.Unsubstituted phenyl radicals are preferred, since the starting compoundtriphenylphosphine used for the synthesis of the ylids is very cheapand, in addition, the reaction yields solid triphenylphosphine oxide,which is very sluggish to react and is easy to separate.

The phosphoranes II serving as starting materials are known or areobtainable in known manner [cf A. Maercker, Org. Reactions, 14, 402(1965), Ramirez and Dershowitz, J. Org. Chem. 22, 41 (1957), G. Wittigand W. Haag, Chem. Ber. 88, 1654 (1955), and O.lsler et al, Helv. Chim.Acta 40, 1242 (1957)], in that a tertiary phosphine and a compoundHal—CH₂—A are reacted to form a phosphonium salt of formula III

R₃P⊕—CH₂—AHal⊖  (III),

in which Hal denotes halogen, particularly chlorine, and this salt isconverted to the phosphorane II by means of a base and without isolationfrom the reaction mixture.

The reaction takes place in an inert and preferably polar solvent ordiluent, advantageously in the same solvent or diluent as is used forthe subsequent chlorination of the phosphorane II.

The amount of solvent used should be such as to ensure that the startingmaterials are completely dissolved. It is normally adequate to use thesolvent in an amount which is from 5 to 10 times the amount of thetertiary phosphine.

To ensure complete conversion, it is necessary to use at least equimolaramounts of tertiary phosphine and α-haloacyl derivative, although aslight excess of up to about 10% molar of one or the other of thesereactants is acceptable.

In general, atmospheric pressure is employed, and the reactiontemperature is generally between 20° C. and the boiling temperature ofthe solvent used.

Preferably, the phosphorane II is not isolated from the reaction mixturebefore being subjected to the process of the invention in the same or adifferent reaction vessel.

Examples of suitable solvents or diluents for the phosphorane II arearomatic hydrocarbons such as benzene, toluene, o-, m-, and p-xylene,and nitrobenzene, chlorinated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene,1,2-, 1,3-, and 1,4-dichlorobenzenes, and particularly preferredsolvents are aliphatic and cycloaliphatic alcohols having from 1 to 6carbon atoms, such as methanol, ethanol, n-propanol, isopropanol,n-butanol, isobutanol, n-pentanol, n-hexanol, and cyclohexanol.

Mixtures of alcohol and water containing up to about 40% v/v of water,are also well suited for use as solvents.

The amount of solvent used is not crucial and it will, as a rule, besufficient to use a molar amount of solvent which is from 5 to 10 timesthat of compound II.

According to the invention, the chlorination takes place in the presenceof a mineral base acting as hydrogen chloride acceptor, this being addedto the solution of II at the same time as the chlorine and at the rateat which it is consumed.

Chlorination is preferably effected by the use of pure chlorine gas,although it is possible to use liquid chlorine or mixtures of chlorinegas and inert gases such as nitrogen, argon, carbon dioxide, and steam.In such cases the proportions of the components of the mixture aresuitably from 5 to 50 moles of chlorine per mole of inert gas.

To achieve complete conversion, at least 1.0 mole of chlorine (Cl₂) willbe required for each mole of phosphorane II. It is preferred to useequimolar amounts or slightly more or less than the molar amount (up toca 10% molar) relevant to II.

Suitable mineral bases are salts of weak acids with alkali metals,alkaline-earth metals, or transition metals, which salts react as a basein aqueous solution. Such salts are, primarily, alkali metal andalkaline-earth metal hydroxides, such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, calcium hydroxide, and magnesiumhydroxide, alkaline-earth metal oxides such as magnesium oxide, andalkali metal and alkaline-earth metal salts of weak organic acids suchas carbonic acid, acetic acid, and benzoic acid, eg, sodium carbonate,potassium carbonate, calcium carbonate, sodium bicarbonate, sodiumacetate, and potassium acetate.

Particularly preferred mineral bases are the alkali metal hydroxides,and especially sodium hydroxide and potassium hydroxide.

The mineral base can be used in the form of a suspension or, preferably,an aqueous solution. The amount used is advantageously such that the pHof the reaction mixture does not rise above 9 and is preferably between7 and 8, throughout the reaction. As a rule, 2 equivalents of base permole of phosphorane II suffice.

The reaction temperature is generally between −50° and +50° C.,preferably between −15° and +30 C.

No special pressure conditions are necessary, and it will therefore beusual to carry out the reaction at atmospheric pressure. It is possibleto use a slightly reduced or slightly elevated pressure, but not,normally, to any advantage.

The product is worked up in the usual manner, for example by extractionor filtration. However, it will normally be recommendable to subject theproducts I to further reaction without removing them from the reactionmixture. It is preferred to react them with a carbonyl compound offormula IV

in which R′ and R″ independently denote hydrogen or c-organic radicals[cf, eg, G.Märkl, Chem. Ber. 94, 2996 (1961), EP-A 207,894, EP-A340,708, EP-A 384,199, the Japanese Laid-open Patent Application155,358/84, and the Japanese Patent Kokai 152,465/1985] to give thecorresponding olefinically unsaturated compound of formula V

Particularly preferred carbonyl compounds IV are benzaldehyde,nitrobenzaldehyde, and aminobenzaldehyde,1,2,3,4-tetrahydrophthalimidobenzaldehyde,3-chloro-2-(3-formylphenyl)-4,5,6,7-tetrahydroimidazole and the mono-and dihalogenated derivatives thereof.

The α-chloromethylene-triorganylphosphorane derivatives I which are madeavailable by the process of the invention in a simple manner and in goodyields are valuable intermediates for the synthesis of plant protectantsand pharmaceuticals. They are particularly useful for the synthesis ofcinnamates VI, which are important starting points for herbicides andgrowth regulators (cf, eg, EP-A 300,387 and EP-A 240,659):

In the above formula VI, C denotes the nitro group, the amino group or aprotected amino group such as 1,2,3,4-tetrahydrophthalimido, R¹ denoteshydrogen or halogen, preferably fluorine, R² denotes halogen, preferablychlorine, and R³ denotes hydrogen or C₁-C₄ alkyl.

EXAMPLE 1

Methyl 2,α-dichloro-5-nitrocinnamate

a) Preparation of phosphorane II:

A solution of 157 g (0.6 mole) of triphenylphosphine and 68.4 g (0.59mole) of methyl chloroacetate in 150 ml of methanol was heated at theboil for 2 hours. To the resulting mixture there were added, at 20-25°C., 1050 ml of methanol and 25 ml of 25% w/w aqueous caustic soda.

b) Chlorination of phosphorane II:

42 g (0.59 mole) of chlorine gas were passed through the above solutionwith slight cooling to 15-20° C., whilst the pH was kept at about 7.4 bysimultaneously metering in 25% w/w aqueous caustic soda. On completionof the feed of chlorine gas, the reaction mixture was stirred for afurther hour. The α-chloromethoxycarbonylmethylene triphenylphosphoranethus obtained may be used in situ for further syntheses.

c) Reaction of α-chloromethoxycarbonylmethylene-tripheaylphosphoranewith 2-chloro-5-nitrobenzaldehyde:

To the reaction mixture obtained above, cooled slightly to 15-20° C.,there were added, portionwise, 102 g (0.55 mole) of2chloro-5-nitrobenzaldehyde. The mixture was stirred for 2 hours at20-25° C. and hydrolysis was carried out by the addition of 300 ml ofwater, after which the resulting solids were filtered off, washed twicewith 100 ml of water each time and twice with 100 ml of methanol eachtime, followed by drying under reduced pressure at 50° C. Yield: 75% ofmethyl 2,α-dichloro-3-nitrocinnamate, mp 110-112° C.

EXAMPLE 2

Ethyl α-chloro-4-nitrocinnamate

In a manner similar to that described in Example 1,α-chloroethoxycarbonyl-methylene-triphenylphosphorane was synthesizedfrom 157 g (0.6 mole) of triphenylphosphine and 72.3 g (0.59 mole) ofethyl chloroacetate in ethanol and then chlorinated. To make ethylα-chloro-4-nitrocinnamate, the resulting reaction mixture was reactedwith 83.1 g (0.55 mole) of 4-nitrobenzaldehyde in a manner analogous tothat described in Example 1. Yield: 86%, mp 108-110° C.

EXAMPLE 3

Ethyl 2,α-dichloro-5-nitrocinnamate

a) Synthesis of phosphorane II:

A solution of 157 g (0.6 mole) of triphenylphosphine and 72.3 g (0.59mole) of ethyl chloroacetate in 150 ml of ethanol was heated at the boilfor 2 hours. To the resulting mixture there were added, at 20-25° C.,800 ml of ethanol, 200 ml of water, and 10 ml of 50% w/w aqueous causticsoda.

b) Chlorination of phosphorane II:

42 g (0.59 mole) of chlorine gas were passed through the above solutionwith slight cooling to 15-20° C., whilst the pH was kept at about 7.4 bysimultaneously metering in 25% w/w aqueous caustic soda. On completionof the feed of chlorine gas, the reaction mixture was stirred for afurther hour. The α-chloroethoxycarbonylmethylene-triphenylphosphoranethus obtained may be used in situ for further syntheses.

c) Reaction of α-chloroethoxycarbonylmethylene-triphenylphosphorane with2-chloro-5-nitrobenzaldehyde:

To the reaction mixture obtained above, cooled slightly to 15-20° C,.there were added, portionwise, 102 g (0.55 mole) of2-chloro-5-nitrobenzaldehyde. The mixture was stirred for 2 hours at20-25° C. and hydrolysis was then carried out by the addition of 120 mlof water, after which the resulting solids were filtered off, washedtwice with 100 ml of water each time and twice with 100 ml of methanoleach time, followed by drying under reduced pressure at 50° C. Yield:88% of methyl 2,α-dichloroethoxycarbonyl, mp 96-98° C.

What is claimed is:
 1. A process for the preparation ofα-chloromethylene-triorganylphosphorane derivatives of the formula I

in which the radicals R can be the same or different and denoteC-organic substituents and A stands for cyano or a group CO-B where B isa C-organic or O-organic radical which has from 1 to 12 carbon atoms andis inert under chlorination conditions, by chlorination of phosphoranesof formula II

with chlorine, wherein the chlorination is carried out in the presenceof an alkali metal hydroxide as hydrogen chloride acceptor and thechlorine and said base are fed to the reaction mixture concurrently butseparately at the rates at which they are consumed, such that the pHdoes not rise above 9 throughout the reaction.
 2. A process as definedin claim 1, wherein the starting material is a mixture of phosphorane IIand an inert solvent such as is obtained when said II is synthesizedfrom a tertiary phosphine and a compound of the structure Hal—CH₂—A,where Hal denotes halogen, with subsequent reaction of the resultingphosphonium salt with a base.
 3. A process as defined in claim 1,wherein the chlorination is carried out using undiluted chlorine gas. 4.A process as defined in claim 1, wherein the chlorination is carried outin a lower alcohol acting as solvent.
 5. A process for the preparationof olefinically unsaturated compounds of formula V

in which R′ and R″ denote hydrogen or C-organic radicals whichcomprises: reacting a α-chloromethylene-triorganylphosphorane derivativeI

in which the radicals R can be the same or different and denoteC-organic substituents and A stands for cyano or a group CO-B where B isa C-organic or O-organic radical which has from 1 to 12 carbon atoms andis inert under chlorination conditions, with a carbonyl compound IV

wherein the derivative I is present in the reaction mixture formed bythe process defined in claim
 1. 6. A process for the preparation ofolefinically unsaturated compounds of formula V

in which R′ and R″ denote hydrogen or C-organic radicals, by thereaction of a α-chloromethylene-triorganylphosphorane derivative I

in which the radicals R can be the same or different and denoteC-organic substituents and A stands for cyano or a group CO-B where B isa C-organic or O-organic radical which has from 1 to 12 carbon atoms andis inert under chlorination conditions, with a carbonyl compound IV

wherein the derivative I is present in the reaction mixture formed bythe process defined in claim
 2. 7. A process as defined in claim 1,wherein the alkali metal hydroxide is sodium hydroxide.